Summary

The second EMBO workshop on `Semaphorin function and mechanisms of action',
held in the gorgeous surroundings of the 12th Century Abbaye des Vaulx de
Cernay near Paris, France this May, brought together a wide range of
scientists working in diverse systems with a common interest: the semaphorins.
Emerging new themes discussed at the meeting included the recognition of an
increasingly complex way in which different cells regulate responsiveness, and
the significance of considering semaphorins in the pathology of various
diseases.

Introduction

At the outset of scientific interest in the semaphorins, they tended to be
thought of as growth cone `collapsing factors' or as inhibitory guidance cues
that are essential for nervous system development. This important, but
somewhat limited, view of these molecules has since evolved, as semaphorins
also play pivotal roles in the immune and vascular system, control the
movement of neural crest cells, regulate cardiac and skeletal development, and
are involved in tumour growth and cancer cell metastasis. Correspondingly,
research into semaphorins has expanded significantly over recent years, and,
only 10 years after the founding members of this group `collapsin' and
`fasciclin IV' were identified (Kolodkin et
al., 1992; Luo et al.,
1993), the first EMBO workshop was held on Corsica in 2003. In May
2008, Valerie Castellani (University of Lyon, France), Alain Chedotal
(Institute de la Vision, Paris, France) and Alex Kolodkin (Johns Hopkins
University School of Medicine, Baltimore, MD, USA) organised the next EMBO
meeting in this field and gathered together scientists involved in analysing
the various aspects of semaphorin biology in the beautiful setting of the
Abbaye des Vaulx de Cernay (see Fig.
1).

The closing lecture of the meeting given by Hajime Fujisawa provided a very
insightful account of the discovery of the semaphorin receptors, neuropilin
and plexin, and their function in neural development. Now a Professor Emeritus
of Nagoya University, Fujisawa has played a central role in the foundation of
research into these membrane proteins. When neuropilin 1 was identified as an
essential binding receptor for Class III semaphorins
(He and Tessier-Lavigne, 1997;
Kolodkin et al., 1997),
Fujisawa had already recognized its function as a cell surface protein (the A5
antigen) that is expressed on specific subsets of axons in the developing
Xenopus nervous system (Fujisawa
et al., 1990; Takagi et al.,
1991; Takagi et al.,
1987). As it turned out, his B2 antigen was later identified as a
plexin. Since then, more components of functional semaphorin receptor
complexes have been identified, mediating a diverse range of responses in
different cell types, which was a recurring topic of discussion at this
interesting meeting.

Regulating responsiveness at the receptor level

Fanny Mann (Development Biology Institute of Marseille, Luminy, France)
reported on the divergent cellular responses evoked by Sema3E (see
Fig. 2 for more on semaphorin
nomenclature), which is known to require the plexin D1 receptor and can
function - unusually for Class III semaphorins - independently of neuropilins.
Her previous work in mice indicates that neurons of the subiculum, which form
the major output tract of the hippocampus, and cortical neurons use plexin D1
to transduce Sema3E signalling. However, the presence of neuropilin 1 in
subicular neurons robustly transforms the repulsive signal mediated by plexin
D1 into an attractive one (Chauvet et al.,
2007). A convincing investigation by Mann into the downstream
signalling stirred interest in this curious Class III semaphorin. She reported
that, in cortical neurons, repellent Sema3E antagonises the phosphorylation of
Akt and of Gsk3 (glycogen synthase kinase 3) through the downregulation of
PI3K (phosphoinositide 3-kinase), involving the intrinsic RasGAP (Ras GTPase
activating protein) activity of plexin D1. In subiculum neurons, however, Mann
found that the effect of Sema3E on increasing neurite length appeared to be
independent of the plexin-RasGAP activity, which may highlight the presence of
an alternative transducing receptor for Sema3E attractive responses. Her
favoured candidate is Vegfr2 (vascular endothelial growth factor receptor 2),
which she showed is readily expressed in the neurons of the subiculum.
Evidence for a further bifunctional role of Class III semaphorins was
presented by Jeroen Pasterkamp (University Medical Centre Utrecht, The
Netherlands). His careful analysis of the formation of the mesodiencephalic
dopamine system in mice revealed that neurons of the ventral tegmental area
(VTA) appear to be distinct, not only on the anatomical, but also on the
molecular, level. For example, whilst rostrally located VTA neurons are
repelled by Sema3C, Sema3F evokes attractive responses in this specific
neuronal population. By contrast, Sema3F mediates the repulsion of caudally
located VTA neurons. Not only do Pasterkamp's results exemplify another
semaphorin that exerts dual responses, they will undoubtedly create invaluable
information on the development of a key neuronal circuit that is affected in
neurodegenerative and neurodevelopmental diseases, such as Parkinson's disease
and schizophrenia. Oded Behar (The Hebrew University, Israel) focused his talk
on a completely different branch of responses that can be evoked by
semaphorins, the induction of neuronal apoptosis. In mice, loss of plexin A3
causes the complete failure of Sema3A to induce death responses in dorsal root
ganglion (DRG) neurons, whilst - at the same time - Sema3A responses in the
collapse assay are preserved. His work suggests that Sema3A-mediated cell
death and guidance in the same cell type requires different functional
receptor complexes.

Repulsive semaphorins expressed in the vicinity of larger bundles of axons,
the axonal fascicles, have classically been thought to function by creating an
inhibitory territory, which actively pushes axons to extend in tight bundles.
It was surprising, then, to hear Mary Halloran (University of
Wisconsin-Madison, WI, USA) introduce the idea that Sema3D regulates axon-axon
interaction in a slightly different way. She investigates the pathfinding of
axons that form the medial longitudinal fascicle (MLF, see
Fig. 3D) in zebrafish, a major
axon tract that connects the midbrain and the spinal cord. In this system,
posteriorly located neurons extend axons first, whereas subsequent axons move
on preformed fascicles. MLF neurons express the zebrafish neuropilin 1A and
the cell adhesion molecule (CAM) L1, whilst Sema3D expression borders their
trajectory. This expression pattern has led to the idea that Sema3D might
promote MLF fasciculation by repulsion. Unexpectedly, patches of Sema3D,
expressed ectopically in the MLF path, were insufficient to divert axons.
Halloran's analysis reveals that Sema3D affects fasciculation by regulating
the levels of L1 expression and axon-axon adhesion. Whilst morpholino
knockdown of Sema3D reduces L1 expression, its overexpression increases the
surface expression of L1 in MLF axons
(Wolman et al., 2007). In
addition to L1, other CAMs, such as Tag1 (transiently expressed axonal
glycoprotein 1), might be required for proper axon-axon interactions and for
the guidance of MLF neurons (Wolman et
al., 2008), demonstrating that the formation of even a relatively
simple tract is governed by the concerted action of numerous components.
Halloran's work is undoubtedly of wider significance, as it promises to inform
the investigation of other systems. Improper fasciculation may turn out to be
the underlying cause of several defects frequently referred to as `guidance
defects'.

Flagging the Sema code. From the left, Hajime Fujisawa and the three
meeting organisers Alain Chedotal, Alex Kolodkin and Valerie Castellani in
front of the Abbaye des Vaulx de Cernay, where the second EMBO workshop on
`Semaphorin function and mechanisms of action' was held. Photo courtesy of
B.J.E.

The midline never fails to attract

It is not surprising that guidance mechanisms involved at the ventral
midline of the developing spinal cord have become a focus of the molecular
analysis of semaphorin function. Axons of the dorsally located commissural
neurons travel ventrally, leading them to an intermediate target - the floor
plate - before turning sharply in the ventral funiculus of the spinal cord
white matter. Secreted Sema3B, which is expressed in the floor plate, has
previously been shown to be essential for regulating the proper guidance of
commissural axons during and after their crossing of the floor plate
(Zou et al., 2000), and work
presented by Homaira Nawabi (University of Lyon, France) focussed on the
cellular regulation of Sema3B in the mouse spinal cord. Based on the
observation that commissural neurons gain sensitivity to Sema3B only following
incubation with floor plate-conditioned medium, Nawabi analysed expression of
the receptors that are likely to be involved in this switch. Her data show
that plexin A1 appears to be present in the distal segment of commissural
axons only, precisely from the moment when axons traverse the floor plate,
which indicates a potential involvement of this plexin in increasing the
sensitivity of axons to Sema3B. In her search for an underlying mechanism that
controls this localised expression, Nawabi's work suggests that plexin A1 is a
target of intra-neuronal proteolytic cleavage in pre-crossing axons. Sharply
at the floor plate, this cleavage activity is inhibited, and commissural
neurons gain plexin A1 expression and responsiveness to Sema3B.

Work presented by Greg Bashaw (University of Pennsylvania School of
Medicine, PA, USA) highlighted another way in which midline crossing is
co-ordinated by a tightly woven network of different cellular events. In the
Drosophila midline, Commissureless (Comm) controls the midline
crossing of commissural neurons through the regulation of the Roundabout
(Robo) receptor on pre-crossing axons. Much progress has been made in the
analysis of Comm expression and function, and the effect it has on Robo. By
contrast, much less is known concerning the regulation of Comm itself. Here,
Bashaw made the intriguing observation that mRNA levels of Comm are affected
in flies deficient in the attractive Netrin receptor Frazzled. As a
consequence, one would naturally propose that the Netrin/Frazzled interaction
positively regulates Comm transcription and midline crossing. However - in a
finding that shows the midline remains full of surprises -
NetA/NetB double mutant flies exhibit no reduction in
Commissureless mRNA, suggesting that the Netrin receptor Frazzled fulfils a
dual purpose, evoking Netrin-dependent responses (axon attraction) and
Netrin-independent responses (activation of Commissureless transcription). One
wonders if Semaphorins or their receptors will also be identified as being
mediators of transcriptional activity in the context of axon guidance.

Compartmentalisation of semaphorin transducers in time and space

Much of what we currently understand about the signalling mechanisms that
are activated by semaphorins is based on extended biochemical analysis and, in
many cases, the analysis of cellular systems that exploit techniques that
force the overexpression (activation) or the loss of expression (activity) of
specific components of a signalling pathway. Along this vein, the work
presented by Manabu Negishi (Kyoto University, Japan) analysed the signalling
events downstream of Sema4D/plexin B1 hippocampal neurons of the rat.
Following ligand stimulation, he reported on the rapid loss of (activatory)
phosphorylated Akt and (inhibitory) phosphorylated Gsk3, which regulates Crmp2
(collapse response mediator protein 2), thereby potentially affecting
microtubule dynamics (Ito et al.,
2006). Although it has been proposed that similar signalling
relationships mediate responses by Sema3A
(Chadborn et al., 2006;
Eickholt et al., 2002) and
Sema3E (as presented in the talk by Fanny Mann), the question of how Akt/Gsk3
is controlled provoked some controversy at the meeting. Unquestionably, the
intrinsic GTPase activity of plexin B1 (which is found in all plexin family
members A-D) and the activity of its substrate R-Ras are crucial in
antagonising PI3K upstream of Akt. However, all three (Negishi, Eickholt and
Mann) agreed that the 3-phosphatase PTEN is also an essential component of the
regulation of semaphorin signalling and its functional responses. Whilst
Negishi's work proposes that C-terminal phosphorylation of PTEN regulates the
activity of the phosphatase in his specific system, Eickholt's presentation
proposed a model in which changes in the subcellular distribution of PTEN is
important in regulating responsiveness. Clearly, further analysis is required
to fully comprehend the control of PTEN in the semaphorin pathway, which
promises to be an exciting avenue for future work. James Zheng (University of
Medicine and Dentistry of New Jersey, NJ, USA) presented a case for the
compartmentalisation of signalling being crucial for semaphorin responses. He
concentrated on the `A kinase anchoring proteins' (AKAPs), which function as a
molecular scaffold and can anchor enzymes, bringing them into close proximity
with their respective effectors (and/or affectors). Zheng has shown
previously, for example, that the spatial targeting of PKA to growth cone
filopodia is mediated by AKAP and that interference with this association
impairs cAMP-mediated attractive turning responses
(Han et al., 2007). AKAP is
also important for the Sema3A-mediated repulsion of Xenopus growth
cones. However, Zheng's result suggests that its involvement is independent of
PKA and potentially involves the ERM (ezrin, radixin and moesin) proteins.

The semaphorin family of proteins. The known members of the
semaphorin family have been categorised into 8 classes (V-7). All semaphorins
share a ∼500 amino acid semaphorin (Sema) domain, which is followed, in
some classes, by a single Ig-like domain. Several members of the semaphorin
family are secreted molecules with no membrane attachment site (for example
Class 2 and Class 3 semaphorins), whereas others are linked to the cell
surface by a transmembrane domain or by a GPI anchor. One subfamily, the Class
5 semaphorins, contains a set of thrombospondin type I repeats. Adapted, with
permission, from the Semaphorin Nomenclature Committee
(Semaphorin Nomenclature Committee,
1999).

Semaphorins control protein synthesis in axon guidance and
morphogenesis

Two talks demonstrated the ability of semaphorins to regulate the
translation of specific subsets of mRNA, and it was striking that in two
fairly divergent systems - Xenopus retinal ganglion cell growth cones
and epithelial rays of the nematode worm - a common functional target of
semaphorin function is the cell's translational machinery. In the first of
these talks, Christine Holt (Cambridge University, UK) investigated the
possibility that specific sets of protein are translated in the growth cone in
response to guidance cues, including Sema3A. Indeed, her earlier work has
provided evidence that protein synthesis is required for Sema3A growth cone
collapse (Piper et al., 2006).
One likely target of localised Sema3A-induced translation in growth cones is
the actin filament severing factor ADF/Cofilin. She suggests that the
Sema3A-induced, spatially restricted synthesis of ADF/Cofilin may distort
normal actin dynamics sufficiently in order to induce collapse responses.
Akira Nukazuka (Nagoya University, Japan) discussed similar findings from his
work on semaphorin function during ray morphogenesis in Caenorhabditis
elegans. Each ray is composed of four cells, the hypodermis, a structural
cell and two neuronal cells, and ray assembly requires the two worm
semaphorins SMP-1/SMP-2 and their Plexin receptor, Plexin 1. From an unbiased
screen for suppressors of the plexin 1-/- ray phenotype,
Nukazuka isolated a negative regulator of translation initiation, GCN-1, which
inhibits mRNA translation initiation by participating in the phosphorylation
of eIF2α (eukaryotic translation initiation factor 2α). To
investigate whether semaphorin regulates eIF2α phosphorylation in vivo,
he then used the power of worm genetics. He expressed Flag-eIF2α
specifically in rays and analysed phosphorylation levels following the
retrieval of the Flag-tagged proteins. His results show that plexin
1/Smp-1/Smp-2 mutants have substantially elevated levels of
phosphorylated eIF2α in their rays compared with wild-type worms
(Nukazuka et al., 2008). As
the knockdown of ADF/cofilin phenocopies plexin
1/Smp-1/Smp-2 mutants, it appears that the actin-severing
protein may be a key target of semaphorin-induced translation, as in the
research presented by Holt. Although it is difficult to see how rapid changes
in growth cone dynamics and a morphogenic programme use similar signalling
systems, the overlap in results is compelling. It remains to be seen, however,
if the translation of specific subsets of mRNA, especially those involved in
cytoskeletal regulation and the control of growth cone motility, contribute to
the assembly of neuronal circuits in vivo.

Shaping neuronal circuits

The talks discussed thus far portrayed the multifaceted way in which
semaphorins use cellular mechanisms to guide axons to their appropriate
synaptic targets. But their involvement in assembling proper neuronal circuits
does not stop there. It is apparent that semaphorins also regulate
synaptogenesis, dendrite morphogenesis, and the removal (pruning) of excess
axons. In this context, David Ginty (Johns Hopkins University School of
Medicine, USA) provided invaluable information on the function of Sema3A and
Sema3F during cortical and hippocampal circuit formation. His work - a
collaboration with Alex Kolodkin - shows that Sema3a-/-
and neuropilin 1-/- mice exhibit defects in the elaboration of
basal dendrites in the cortex, whilst apical dendrites appear normal. Similar
phenotypes are seen in plexin A4-/- mice, suggesting that Sema3A
exerts its function on cortical dendrite development through a neuropilin
1/plexin A4 receptor complex. This is in contrast to the defects that occur in
Sema3f-/- or neuropilin 2-/- mice, which
exhibit striking increases in the number and length of dendritic spines in
granule cell neurons of the hippocampus, a phenotype also present in layer-5
pyramidal neurons of the cortex. Electron microscopy analysis reveals the
presence of spines with enlarged post-synaptic densities that appear to form
multiple synapses. The loss of plexin A3 phenocopies this defect, revealing
that Sema3F controls synapse development through neuropilin 2 and plexin A3.
Thus, Sema3A appears to control cortical neuronal morphogenesis, regulating
appropriate basal dendrite development, whereas Sema3F signalling restricts
the growth of dendritic spines.

The talk presented by Hwai-Jong Cheng (University of California at Davis,
CA, USA) provided a neat example of how different semaphorins function in a
context-dependent fashion that is important at later stages of development
during circuit formation. His model system, the corticospinal tract (CST) of
mice, is characterised by the presence of several transitory connections that
are established in inappropriate locations. For example, a transient component
of the developing CST arises in the visual cortex, whereas pyramidal neurons
from the motor cortex make connections with the superior colliculus of the
visual system. Cheng finds that in plexin A3/plexin A4 double mutant mice, the
visual CST fails to be pruned, with un-pruned neurons maintaining synaptic
contacts in the spinal cord. By contrast, the pruning of the motor
corticospinal component in these mice is not affected. His results further
suggest that the stereotyped pruning of the visual CST is likely to be
regulated by Sema3F (Low et al.,
2008).

The development of two other circuits - the limbic and the cortical
circuits - was discussed by Kevin Mitchell (Trinity College Dublin, Ireland).
He performed a careful comparative expression analysis of Sema6A, plexin A2
and plexin A4, and related these data with the phenotypes that occur as a
result of loss of these components in mice. His data indicate that Sema6A and
plexin A2/plexin A4 are often co-expressed, and that the phenotypes of Sema6A
and plexin A2/plexin A4 mutant mice are not always suggestive of a classical
ligand-receptor relationship. Indeed, there is evidence that Sema6A may be
involved in bidirectional signaling and that interactions in cis may be
important in vivo. Single plexin A mutant phenotypes also tend to reflect
Sema6 function more than Sema3 function. Sema6A mutants exhibit widespread
defects in cell migration and axon guidance, including some that directly
parallel pathological changes observed in schizophrenia, for example, a
reduction and decreased fasciculation of the fornix, and altered
thalamocortical connectivity, which leads Mitchell to propose that Sema6A
mutants might serve as a model for the study of this psychiatric disorder.
Using EEG recordings, Mitchell showed that Sema6A-null mice exhibit increased
brain activity, which is blocked by clozapine, an antipsychotic drug for
treating schizophrenia. Behavioral defects in these mice also include
hyperlocomotion (again reversible by clozapine), altered social interaction
and decreased anxiety.

Liqun Luo (Stanford University, CA, USA) summarised the function of Sema-1a
and Sema-2a in the wiring of olfactory circuits in Drosophila. In
this system, olfactory sensory receptor neurons (ORNs) in the antenna project
to the antennal lobe in a highly organized fashion, and connect with distinct
synaptic glomeruli in the central nervous system. His work demonstrates that
the transmembrane semaphorin Sema-1a is required for the proper axon targeting
of a subset of ORNs, mediating axonal segregation most likely through
axon-axon repulsion (Sweeney et al.,
2007). In addition, there exists a graded distribution of Sema-1a
in the antennal lobe, where it acts as a receptor and instructs the targeting
of the dendrites of olfactory projection neuron (PNs)
(Komiyama et al., 2007).
Brain-derived secreted Sema-2a, however, appears to be required for ORN axon
targeting.

Functions of semaphorins in cancer and the immune system

Several participants discussed the role of semaphorins in tumour
progression, cancer cell metastasis, and in immune responses, which will be
summarised - given the interests of the readership of Development -
only briefly here. Semaphorins have become a major target for the development
of therapeutics for treating malignancies and autoimmune diseases. Gera
Neufeld's talk (Israel Institute of Technology, Israel) was oriented by
questions as to why Sema3B, expressed in HEK293 or cancer cells, exerts
relatively weak repulsion on endothelial cells. He finds that the weak
response is caused by an inactivation of Sema3B through furin-like
pro-convertase-dependent cleavage of the protein. A furin-resistant Sema3B
exerts inhibitory function on endothelial cell tube formation, which
identifies Sema3B as an anti-angiogenic factor. Given that furin activities
are increased in a number of cancers, this work highlights an example in which
cancer cells have adopted strategies that enable tumour progression by
overcoming factors that inhibit angiogenesis. Neufeld's presented work also
identified additional Class III semaphorins, including Sema3A, Sema3D, Sema3E
and Sema3G, as being anti-tumorigenic factors with anti-angiogenic
properties.

In his presentation, Luca Tamagnone (University of Torino, Italy)
considered a mechanism that clarified other questions concerning the function
of Sema3B. While Sema3B has been classified as a putative tumour suppressor
gene, there is no clear correlation between loss of Sema3B and tumour
development. As a matter of fact, he finds that although Sema3B overexpression
delays tumour growth in nude mice, it actually increases metastatic
dissemination to the lungs. Notably, Sema3B is ineffective in increasing the
motility or invasiveness of cancer cells in vitro. Here, an indirect
mechanism, involving Sema3B-induced changes of the tumour microenvironment
solves the controversy. Tamagnone shows that Sema3B expression increases the
production of Il8 (interleukin 8) by cancer cells, a cytokine that is known to
regulate infiltrating leucocytes and endothelial cells in the tumour stroma
and to promote metastatic progression
(Rolny et al., 2008).

Anil Bagri (Genentech, CA, USA) presented an exceptionally promising
therapeutic approach for the treatment of malignancies. The lymphatic
vasculature is an important route for the distribution of metastasising cancer
cells, and a key factor that controls the sprouting of lymphatic vessels is
Vegfc. Neuropilin 2 functions as a Vegfc co-receptor and, thus, interfering
with this receptor was hypothesised to impede the formation of lymphatics that
is associated with tumours. As the Vegf association with neuropilin 2 is
mediated by the b1/b2 domain of neuropilin 2 (which is not targeted by
semaphorins), the Genentech group generated a high-affinity antibody specific
to this domain. The results offered by Bagri demonstrate that anti-neuropilin
2 treatment is effective in inhibiting the formation of functional lymphatics
associated with tumours in mice, thereby attenuating the development of
metastasis (Caunt et al.,
2008). However, because treatment with the antibody did not cause
a significant reduction in tumor size, a combined use of this therapeutic tool
in association with tumor growth-inhibiting drugs may be warranted. This
notwithstanding, the talk signifies that neuropilin 2 is an excellent target
for modulating metastasis in humans.

Hitoshi Kikutani (Osaka University, Japan) presented his work on
investigating the immune responses that are mediated by Sema4A and the
GPI-anchored Sema7A - an, as yet, less-characterised semaphorin that has
previously been found to promote axon outgrowth through β1 integrin
receptors (Pasterkamp et al.,
2003). Through functional α1/β1 integrins, Sema7A
functions as a potent stimulator of monocytes and macrophages. Kikutani
demonstrates further that α1 integrin-deficient macrophages exhibit
reduced responses to Sema7A, and that Sema7A-/- mice are
defective in cell-mediated immune responses, including experimental autoimmune
encephalomyelitis, in the presence of normal T-cell development and migration.
Because Sema7A-/- T-cells fail to induce contact
hypersensitivity, Kikutani's work suggests that Sema7A functions locally at
the site of inflammation (Suzuki et al.,
2007). The loss of Sema4A in immune cells, by contrast, leads to
the impaired differentiation of type 1 helper T-lymphocytes, and a fraction of
Sema4A-/- mice spontaneously develop atopic
dermatitis-like skin lesions.

Conclusion

In conclusion, the organisers of the meeting provided an excellent and
stimulating programme, which clearly highlighted the current and emerging
trends in the field. Undoubtedly, they achieved their goal in fostering
discussion, exchanging ideas and facilitating the establishment of new
collaborations among scientists working on different eaxperimental systems
involving semaphorins. Such `mixed system - same molecule' conferences are
extremely valuable in this respect, and also support the development and the
dissemination of tools in the field. We certainly look forward to the next
semaphorin workshop, not least because it might involve clarification of some
of the interesting and divergent findings and views prefigured by this
one.

Acknowledgments

I would like to thank all of the participants in this conference for their
stimulating discussions. I am very grateful to all of the speakers discussed
for their permission to reproduce their work and for their helpful feedback.
Unfortunately, due to space limitations, I was unable to include all of the
presentations in this report. Special thanks are due to Luca Tamagnone and
Alex Kolodkin for commenting on the text.

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